Application Of A Receptor Pruning Methodology To The Enoyl-acp Reductase From Escherichia Coli (fabi)

Receptor pruning is an approach for achieving reasonable conformational ensemble profile in terms of time and computational resources. The purpose of this study is to reduce the size of a model structure of enoyl-acp reductase (ENR) from E. coli, FabI, to allow ligand-receptor molecular dynamic (MD) simulations to be computationally economical yet still provide meaningful binding thermodynamic data. Three reduced-size models of FabI were created by pruning away all residues greater than 12, 10 and 8 Å radius. The largest ligand was docked in the active site to define the largest required receptor model. Energy minimization and MD simulations were carried out using the MOLSIM 3.2 program. The lowest energy structure for each of receptor models from MD calculation was compared by root mean square (RMS) fit to the equivalent portion of the crystal structure of FabI. A scale-down 12 Å receptor model of the enzyme FabI maintains the structural integrity of the composite parent crystal structure. The perspectives include the structure-based design of new antituberculosis agents regarding the similarity in the active site of two ENRs, FabI and InhA (M. tuberculosis). © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.257629636Grassberger, M.A., Turnowsky, F., Hildebrandt, J., (1984) J. Med. Chem., 27, pp. 947-953Baldock, C., Rafferty, J.B., Sedelnikova, S.E., Baker, P.J., Stuitje, A.R., Slabas, A.R., Hawkes, T.R., Rice, D.W., (1996) Science, 274, pp. 2107-2110Baldock, C., De Boer, G.J., Rafferty, J.B., Stuitje, A.R., Rice, D.W., (1998) Biochem. Pharmacol., 55, pp. 1541-1549Bergler, H., Fuchsbichler, S., Högenauer, G., Turnowsky, F., Eur. J. Biochem., 19, p. 242Stewart, M.J., Parikh, S., Xiao, G., Tonge, P.J., Kisker, C., (1999) J. Mol. Biol., 290, pp. 859-865Rozwarski, D.A., Vilchèze, C., Sugantino, M., Bittman, R., Sacchettini, J.C., (1999) J. Biol. Chem., 274, pp. 15582-15589Kater, M.M., Koningstein, G.M., Nijkamp, H.J.J., Stuitje, A.R., (1994) Plant Mol. Biol., 25, pp. 771-790Magnuson, K., Jackowski, S., Rock, C.O., Cronan Jr., J.E., (1993) Microbiol. Rev., 57, pp. 522-542Barry III, C.E., Lee, R.E., Mdluli, K., Sampson, A.E., Schroeder, B.G., Slayden, R.A., Yuan, Y., (1998) Prog. Lipid Res., 37, pp. 143-179McCarthy, A.D., Hardie, D.G., (1984) Trends Biochem. Sci., 9, pp. 60-63Pasqualoto, K.F.M., Ferreira, E.I., (2001) Curr. Drug Targets, 2, pp. 427-437Pasqualoto, K.F.M., Ferreira, E.I., Santos-Filho, O.A., Hopfinger, A.J., (2004) J. Med. Chem., 47, pp. 3755-3764Tokarski, J.S., Hopfinger, A.J., (1997) J. Chem. Inf. Comput. Sci., 37, pp. 779-791Hopfinger, A.J., Wang, S., Tokarski, J.S., Jin, B., Albuquerque, M.G., Madhav, P.J., Duraiswami, C., (1997) J. Am. Chem. Soc., 119, pp. 10509-10524Albuquerque, M.G., Hopfinger, A.J., Barreiro, E.J., Alencastro, R.B., (1998) J. Chem. Inf. Comput. Sci., 38, pp. 925-938Ravi, M., Hopfinger, A.J., Hormann, R.E., Dinan, L., (2001) J. Chem. Inf. Comput. Sci., 41, pp. 1587-1604Santos-Filho, O.A., Hopfinger, A.J., (2002) Quant. Struct.-Act. Relat., 43, pp. 324-336Hong, X., Hopfinger, A.J., (2003) J. Chem. Inf. Comput. Sci., 43, pp. 324-336Pan, D., Tseng, Y., Hopfinger, A.J., (2003) J. Chem. Inf. Comput. Sci., 43, pp. 1591-1607Pan, D., Jianzhong, L., Senese, C., Hopfinger, A.J., Tseng, Y., (2004) J. Med. Chem., 47, pp. 3075-3088Berstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Tasumi, M., (1977) J. Mol. Biol., 112, pp. 535-542Weiner, S.J., Kollman, P.A., Nguyen, D.T., (1986) J. Comput. Chem., 7, pp. 230-252(2000) HyperChem Program Release 6.03 for Windows, , Hybercube, Inc., Gainesville, FLDoherty, D., (1997) MOLSIM: Molecular Mechanics and Dynamics Simulation Software. User's Guide, Version 3.2, , The Chem21 Group, Inc., Lake Forest, ILDewar, M.J.S., Zoebisch, E.G., Healy, E.F., Stewart, J.J.P., (1985) J. Am. Chem. Soc., 107, pp. 3902-3909Bodor, N., Gabanyi, Z., Wong, C.K., (1989) J. Am. Chem. Soc., 111, pp. 3783-3786Gavezzotti, A., (1983) J. Am. Chem. Soc., 105, pp. 5220-5225Hopfinger, A.J., (1973) Conformational Properties of Macromolecules, p. 71. , Academic Press, New YorkTurnowsky, F., Fuchs, K., Jeschek, C., Hogenauer, G., (1989) J. Bacteriol., 171, pp. 6555-6565Dessen, A., Quémard, A., Blanchard, J.S., Jacobs, W.R., Sacchettini, J.C., (1995) Science, 267, pp. 1638-164

Rational Approach In The New Antituberculosis Agent Design: Inhibitors Of Inha, The Enoyl-acp Reductase From Mycobacterium Tuberculosis [abordagem Racional No Planejamento De Novos Tuberculostáticos: Inibidores Da Inha, Enoil-acp Redutase Do M. Tuberculosis]

In conjunction with the spread of HIV infection, tuberculosis (TB) has been among the worldwide health threats. Mycobacteria resistance to the drugs currently used in the therapeutics is the main cause of TB resurgence. In view of this severe situation, the new and selective anti-TB design is of utmost importance. Fatty acid biosynthesis is a prokariontes and eucariontes biochemical process that supplies essential precursors for the assembly of important cellular components, such as phospholipids, lipoproteins, lipopolysaccharides, mycolic acids and cellular envelope. However, the biochemical and functional differences between the bacterial and mammals' fatty acid synthetic pathway have endowed the mycobacterial enzymes with distinct properties. These provide valuable opportunities for structure- or catalytic mechanism-based design of selective inhibitors as novel anti-TB drugs with improved properties. The enoyl-reductases are essential enzymes in the fatty acids elongation pathway towards the mycolic acids, the main mycobacteria cell wall constituents, biosynthesis and so they are potential targets to the rational new antimycobacteria drug design. This paper highlights recent approaches regarding the design of new anti-TB agents, particularly, the enoyl-ACP reductase inhibitors.442167179BALDOCK, C., de BOER, G.J., RAFFERTY, J.B., STUITJE, A.R., RICE, D.W., Mechanism of action of diazaborines (1998) Biochem. 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Development And Evaluation Of Amoxicillin Formulations By Direct Compression: Influence Of The Adjuvants On Physicomechanical And Biopharmaceutical Properties Of The Tablets

The amoxicillin 500 mg formulations were developed by direct compression using a 23 factorial design. Eight different formulations were carried out and they were analyzed considering three levels: the type of microcrystalline cellulose (Avicel® PH-102 or Avicel® PH-200), the presence or absence of spray-dried lactose, and the presence or absence of the superdisintegrant agent, croscarmellose sodium. Average weight, thickness and diameter, hardness, friability, amoxicillin concentration (iodometric assay), disintegration time, and dissolution profile were the parameters used for the tablets evaluation. Considering all evaluated parameters, a suitable amoxicillin 500 mg tablet formulation should present the microcrystalline cellulose type Avicel® PH-102 and the superdisintegrant agent, croscarmellose sodium (Ac-disol® SD-711), in its composition.2413947Korolkovas, A., (1988) Essentials of Medicinal Chemistry, 2nd Ed., p. 1216. , New York: Wiley-InterscienceDevani, M.B., Patel, I.T., Patel, T.M., (1992) J. Pharm. Biomed. Anal., 10, pp. 355-358Bird, A.E., (1994) Analytical Profiles of Drug Substances and Excipients, 23, pp. 1-52Carceles, C.M., Escudero, E., Vicente, M.S., Serrano, J.M., Carli, S., (1995) Vet. Quart., 17, pp. 134-138Chogle, P., Gudsoorkar, V.R., Shete, J.S., (1996) East Pharm., 39, pp. 121-123Westphal, J.F., Deslandes, A., Brogard, J.M., Carbon, C., (1991) J. Antimicrob. Chemother., 27, pp. 647-654Sanchez, M.A.C., Pastor, R.M.S., Suarez, A.I.T., (1991) An. Real Acad. Farm., 57, pp. 553-561Enézian, G.M., (1972) Pharm. Acta Helv., 47, pp. 321-363Banker, G.S., Anderson, N.R., (1986) The Theory and Pratice of Industrial Pharmacy, , New York: Lea & FebigerShangraw, R.F., (1989) Pharmaceutical Dosage Forms: Tablets, 1. , New York: Marcel Dekker IncBauer-Brandl, A., Becker, D., (1996) Drug Dev. Ind. Pharm., 22, pp. 417-430Sheth, B.B., Bandelin, F.J., Shangraw, R.F., (1980) Pharmaceutical Dosage Forms: Tablets, 1. , New York: Marcel Dekker IncAnsel, H.C., Popovich, N.G., Allen Jr., L.V., (1995) Pharmaceutical Dosage Forms and Drug Delivery Systems, , Philadelphia: Lea & FebigerDoelker, E., (1993) Drug Dev. Ind. Pharm., 19, pp. 2399-2471Ferrero, C., Muñoz, N., Velasco, M.V., Muñoz-Ruiz, A., Jiménez-Castellano, S.R., (1997) Int. J. Pharm., 144, pp. 11-21(2004) DMS Anti-Infectives - Amoxicillin Trihydrate, Compacted for Direct Compression, , www.dsm.com/en_US/html/dai/amoxicillinfordirectcompression.htmNeto, B.B., Scarminio, I.S., Bruns, R.E., (1995) Planejamento e Otimização de Experimentos, 2 Ed., pp. 61-100. , Editora da UNICAMP(1988) Brazilian Pharmacopoeia, , Part I. General Methods, 4th ed., São Paulo: AtheneuFood and Drug Administration, HHS (1996). Code of Federal. Washington: Office of the Federal regulations. Pp 21, págs. 387-535(1995) Pharmacopoeia of United States of America, , 23th ed., Rockville: United States Pharmacopoeial ConventionDoelker, E., Massuelle, D., Veuillez, F., Humbert-Droz, P., (1995) Drug Dev. Ind. Pharm., 21, pp. 643-661Gordon, M.S., Chatterjee, B., Chowhan, Z.T., (1990) J. Pharm. Sci., 79, pp. 43-47Roberts, R.J., Rowe, R.C., (1986) J. Pharm. Pharmacol., 38, pp. 567-571Martin, A., Swarbrick, J., Cammarata, A., (1993) Physical Pharmacy, , Philadelphia: Lea & FebigerHassan, M.A., Kaloustian, J., Prinderre, P., Ramsi, S.H., Khaled, K.A., El-Faham, T.H., Tous, S.S., Joachim, J., (1996) Pharmazie, 51, pp. 400-403Gordon, M.S., Chowhan, Z.T., (1987) J. Pharm. Sci., 76, pp. 907-90